Life and death of circulating cell-free DNA

Kustanovich, Anatoli; Schwartz, Ruth; Peretz, Tamar; Grinshpun, Albert

doi:10.1080/15384047.2019.1598759

Cited by 357 publications

(327 citation statements)

References 162 publications

(240 reference statements)

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“…cfDNA can be specifically used when tumor tissue is unavailable or insufficient for testing [212]. Liquid biopsy, intended to monitor cancer treatment responses has recently been considered to be a promising noninvasive cancer-related test that puts cell-free tumor DNA to use [213,214]. Moreover, cfDNA is now recognized as a biomarker of absolute novelty in cancer diagnosis.…”

Section: Circulating Free Dnamentioning

confidence: 99%

Tumor microenvironment complexity and therapeutic implications at a glance

et al. 2020

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The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis. The reciprocal cell-cell/ECM interaction and tumor cell hijacking of non-malignant cells force stromal cells to lose their function and acquire new phenotypes that promote development and invasion of tumor cells. Understanding the underlying cellular and molecular mechanisms governing these interactions can be used as a novel strategy to indirectly disrupt cancer cell interplay and contribute to the development of efficient and safe therapeutic strategies to fight cancer. Furthermore, the tumor-derived circulating materials can also be used as cancer diagnostic tools to precisely predict and monitor the outcome of therapy. This review evaluates such potentials in various advanced cancer models, with a focus on 3D systems as well as lab-on-chip devices.

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Section: Circulating Free Dnamentioning

confidence: 99%

Tumor microenvironment complexity and therapeutic implications at a glance

et al. 2020

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“…When a cell dies, DNA is released into the bloodstream in short fragments (approximately 160bp, the length of a nucleosome) [7]. All people are thought to have a low level of cfDNA in their blood [8] [9]. In healthy individuals, cfDNA in the blood likely arises from normal cell turnover.…”

Section: Introductionmentioning

confidence: 99%

Estimating the rate of cell type degeneration from epigenetic sequencing of cell-free DNA

Caggiano

Celona

Garton

et al. 2020

Preprint

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Circulating cell-free DNA (cfDNA) in the bloodstream originates from dying cells and is a promising non-invasive biomarker for cell death. Here, we develop a method to accurately estimate the relative abundances of cell types contributing to cfDNA. We leverage the distinct DNA methylation profile of each cell type throughout the body. Decomposing the cfDNA mixture is difficult, as fragments from relevant cell types may only be present in a small amount. We propose an algorithm, CelFiE, that estimates cell type proportion from both whole genome cfDNA input and reference data. CelFiE accommodates low coverage data, does not rely on CpG site curation, and estimates contributions from multiple unknown cell types that are not available in reference data. In simulations we show that CelFiE can accurately estimate known and unknown cell type of origin of cfDNA mixtures in low coverage and noisy data. Simulations also demonstrate that we can effectively estimate cfDNA originating from rare cell types composing less than 0.01% of the total cfDNA. To validate CelFiE, we use a positive control: cfDNA extracted from pregnant and non-pregnant women. CelFiE estimates a large placenta component specifically in pregnant women (p = 9.1 × 10 −5 ). Finally, we use CelFiE to decompose cfDNA from ALS patients and age matched controls. We find increased cfDNA concentrations in ALS patients (p = 3.0 × 10 −3 ). Specifically, CelFiE estimates increased skeletal muscle component in the cfDNA of ALS patients (p = 2.6 × 10 −3 ), which is consistent with muscle impairment characterizing ALS. Quantification of skeletal muscle death in ALS is novel, and overall suggests that CelFiE may be a useful tool for biomarker discovery and monitoring of disease progression.

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“…We hypothesize the difference could be due to the higher viral load seen in transplant patients and greater rate of production of longer CMV fragments or differences in the epigenetic state of CMV in different hosts or states of reactivation. Alternatively, changes in host immune pressure may affect the kinetics of cfDNA production and degradation, as different mechanisms of cell death may affect the length of DNA fragments released into the blood 36 .…”

Section: Discussionmentioning

confidence: 99%

High-resolution profiling of human cytomegalovirus cell-free DNA in human plasma highlights its exceptionally fragmented nature

Peddu

Bradley

Casto

et al. 2020

Sci Rep

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Human cytomegalovirus (CMV) infections comprise a leading cause of newborn impairments worldwide and are pervasive concerns among the immunocompromised. Quantification of CMV viral loads is increasingly used to guide definitions of CMV disease but standardization of CMV quantitation remains problematic, mostly due to differences in qPCR amplicon sizes between clinical laboratories. Here, we used plasma cfDNA sequencing data from 2,208 samples sent for non-invasive prenatal aneuploidy screening to detect CMV and precisely measure the length of CMV fragments in human plasma. CMV reads were identified in 120 (5.4%) samples. Median cfDNA fragment size derived from CMV was significantly shorter than cfDNA derived from human chromosomes (103 vs 172 bp, p < 0.0001), corresponding to the 3 rd percentile of human cfDNA. Sequencing of cfDNA from seven plasma samples from transplant patients positive for CMV confirmed the extraordinarily short nature of CMV cfDNA fragment size with a median length of 149 bp. We further show that these high-resolution measurements of CMV DNA fragment size accurately predict measured discrepancies in serum viral load measurements by different qPCR assays. These results highlight the exceptionally fragmented nature of CMV cfDNA and illustrate the promise of plasma cfDNA sequencing for quantitating viral loads through detection of fragments that would be unrecoverable by qPCR.

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Life and death of circulating cell-free DNA

Cited by 357 publications

References 162 publications

Tumor microenvironment complexity and therapeutic implications at a glance

Tumor microenvironment complexity and therapeutic implications at a glance

Estimating the rate of cell type degeneration from epigenetic sequencing of cell-free DNA

High-resolution profiling of human cytomegalovirus cell-free DNA in human plasma highlights its exceptionally fragmented nature

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